Development of transplantable mouse models to assess the role of prolactin inducible protein in breast tumorigenesis

Abstract:

Breast cancer (BC), a highly heterogenous disease, is the most prevalent cancer in women. The prolactin inducible protein (PIP) is expressed by over 90% of BCs to varying degrees. Higher PIP expression levels have been shown to correlate with better prognosis and patient response to chemotherapy. Previous studies suggest an immunomodulatory role, however, the role of PIP in BC pathogenesis is unknown. In addition to its role in innate immunity, our laboratory has previously shown that deficiency of PIP is associated with defective type 1 T-helper (Th1) cell immune response, which operates as a critical adaptive immune component for antitumor immunity. Therefore, it was hypothesized that PIP inhibits BC and enhances antitumor immunity. Here, the role of PIP in BC progression was investigated using syngeneic transplantable BC mouse models developed from 4T1 and E0771 mouse BC cell lines. PIP was overexpressed in both cell lines and characterized using a number of in vitro functional assays. Following the transplantation of these lines in syngeneic mice, the impact of PIP expression on breast tumorigenesis in vivo was also assessed with specific focus on tumor onset, growth, size, immune response, and metastasis. In vitro functional assay comparisons revealed no differences in proliferation, migration, and response to anticancer drugs in both cell lines. However, in vivo studies showed that the expression of PIP in 4T1 cells delayed tumor onset, reduced tumor growth, and diminished tumor size. These observations were associated with increased percentages of natural killer cells, dendritic cells and reduced frequency of CD4+IL4+ T cells in the PIP expressing 4T1 tumors. Furthermore, PIP expression in 4T1 cells resulted in elevated lung metastasis, indicating that PIP may play opposing roles in BC. Interestingly, these effects however were not observed in the in vivo E0771 mouse BC model thereby suggesting that PIP may have different effects on different types of BC. These studies provide initial preclinical experimental data to suggest that PIP is an important regulator of breast tumor immunity and potentially, metastasis in mouse models, further expanding our understanding of breast cancer progression.